1. Field of the Invention
The invention generally relates to compounds that are useful for the treatment and/or prevention of Alzheimer's disease, and for diagnostic imaging of Aβ plaques. In particular, the invention provides novel bivalent multifunctional Aβ oligomer inhibitors (BMAOIs) that target multiple risk factors involved in Alzheimer's disease (e.g. Aβ oligomers, oxidative stress, biometals and cell membrane/lipid rafts). The BMAOIs comprise i) a multifunctional Aβ oligomer inhibiting moiety; ii) a cell membrane/lipid raft (CM/LR) anchoring moiety; and iii) a spacer moiety that links i) and ii) together.
2. Background of the Invention
Alzheimer's disease (AD) is a devastating neurodegenerative disease and is the most common cause of dementia. The amyloid-β (Aβ) hypothesis has long been recognized as the main theory in the development of Alzheimers disease (AD) and recently emerging evidence indicate that small, soluble oligomers (AβOs) are responsible for disruption of neuronal synaptic plasticity and the resulting early cognitive impairment associated with AD. Studies of brain samples from AD patients also confirmed the correlation of AβOs with the severity of dementia. Most recently, new evidence has indicated that soluble AβOs can up-regulate tau pathology, which further highlights the importance of AβOs in the pathogenesis of AD. Different types of soluble AβOs have been described using various resources. The heterogeneity of AβOs demonstrated so far might suggest that these multiple Aβassemblies exert their neurotoxicity in a variety of ways such as selective uptake and internalization of AβOs through endocytic process demonstrated in cell models, induction of apoptosis, formation of ion channels, dyshomeostasis of biometals, and mishandling of calcium, among others. Despite the heterogeneity of the underlying mechanisms for Aβ's neurotoxicity, one point of consensus remains clear: the requirement of AβOs. Although some studies have indicated that protofibrils might be intermediates of the final mature fibrils, recent studies have suggested that Aβ oligomerization and fibril formation result from independent pathways. Collectively, these findings suggest AβOs as critical contributors in the development of AD pathology, thus providing compelling support for developing AβO inhibitors as therapeutic agents for the treatment of AD.
Besides the characteristic Aβ plaques and tangles, a loss of biometal homeostasis and increased oxidative damage are two other features consistently found in the brains of AD patients. High concentrations of Cu, Zn and Fe have been found within Aβ deposits in both AD human brains and transgenic mouse models. Furthermore, Aβ has been demonstrated to be a metalloprotein that binds to biometals and Aβ interactions with Cu, Zn and Fe can further induce Aβ aggregation and oligomerization. Particularly, Zn and Cu can readily precipitate AβOs but not Aβ monomers. The fact that glutamatergic synapses release high concentrations of Cu and Zn during neurotransmission may explain why AβOs are the major toxic species that impair synaptic plasticity. Oxidative stress is another early event of AD implicated as an important mediator in the etiology of AD. Transgenic mice studies have showed a correlation of increased oxidative stress and Aβ accumulation. Furthermore, secondarily to Aβ binding to biometals and assembling into oligomers and fibrils, Aβ also reduces these metals to produce reactive oxygen species (ROS) that contributes to most types of oxidative damage noted in AD.
Based on the aforementioned theories, numerous strategies have been developed in the past decade as potential AD treatments. This includes secretase inhibitors, Aβ oligomerization/aggregation inhibitors, immunotherapy, metal-complexing agents, anti-oxidants and anti-inflammation agents (NSAIDs). However, the fact that very few of them moved to clinical trials and none of them has been approved by FDA suggests that targeting a single risk factor is not an ideal strategy for developing treatments for this multifaceted disease. The recent failure of AlzheMed (trimprosate), a small molecule of AβO inhibitor, in phase III confirms this point of view.
Although the mechanism of how nontoxic Aβ converts to the toxic AβOs remains elusive, a wealth of data has implicated the roles of neuronal cell membranes/lipid rafts (CM/LR) in the oligomerization and toxicity of Aβ. Once associated with the membranes, Aβ exhibits an enhanced rate of aggregation that is dependent on pH and metal ion and ganglioside interactions. Recently, evidence has also indicated that lipid rafts, a cell membrane microdomain enriched in cholesterol and sphingolipids, may play important roles in Aβ precursor protein (APP) processing and Aβ oligomerization. Current studies of lipid rafts are mainly based on the isolation of detergent-resistant membrane (DRM) using different detergents like Triton X-100.30 Although it is still debated whether DRM are the same as “real” lipid rafts, studies using DRM analysis have revealed that rafts are involved in a variety of cell functions. Lipid rafts have been demonstrated to accelerate the cell membrane binding of Aβ. On the other hand, destruction of lipid rafts affects Aβ membrane binding and protects cells from Aβ toxicity. Most recently, it has been demonstrated that lipid rafts isolated from rat brain tissue and ganglioside-rich C2C12 cells can accelerate the oligomerization of Aβ. Furthermore, APP and its cleavage enzymes (β- and γ-secretases), monomeric Aβ and AβOs have all been identified in lipid rafts/DRM, suggesting that lipid rafts may be a critical platform for Aβ production and oligomerization. Additionally, biometals, such as Cu, have also been indicated to modulate the interaction of Aβ with membrane rafts. Altogether, it is apparent that CM/LRs are important regulators in AD development.
Even though the multifactorial nature of AD and the lack of a unified theory on its etiology have heretofore significantly stymied conventional drug discovery approaches, these difficulties may, however, present an opportunity by suggesting a more efficient and novel way to treat AD by targeting multiple contributors to AD etiology with a single molecule.